Abstract This project addresses areas of need described in PA-16-233 ?Prescription Drug Abuse? examining risks for transition from therapeutic use to misuse, and effective prevention or risk reduction approaches for prescription opioids. Over 51 million Americans undergo surgery annually, and opioids are a mainstay for pain management. Opioids prescribed for surgery often instigate long-term use, and precipitate opioid misuse. Surgery represents a critical event where the majority of patients require opioids regardless of prior opioid- related adverse events, and patients taking opioids prior to surgery require higher doses over extended periods compounding risks. Prior research identifies elevated depressive symptoms as a significant predictor of prolonged postoperative opioid use. Also, patients with preoperative depression or opioid use may be at increased risk for opioid misuse after surgery. Aim 1) of the project will characterize the relationship between preoperative depressive symptoms and opioid use/misuse after surgery by utilizing a perioperative learning healthcare system. The project aims to broadly assess pre-surgical patients for depressive symptoms, and to characterize subsequent opioid-related risks by tracking longitudinal outcomes via the Collaborative Health Outcomes Information Registry-CHOIR system. A prospective cohort of 558 patients, undergoing any elective surgery, will undergo baseline and longitudinal testing via CHOIR (including NIH PROMIS measures of emotional distress). After surgery, participants will report weekly changes in opioid use, opioid misuse, pain, and adverse events for 1 year. We will compare targeted psychological screening via CHOIR to surveillance of routinely available data on depression and antidepressant use in electronic health records (EHRs). We will leverage free text existing in EHRs using data mining algorithms, and correlate self-reported opioid cessation and opioid misuse with data from California?s prescription drug monitoring program (CURES 2.0). Aim 2) will evaluate the relative efficacy of enhanced usual care (EUC) vs. motivational interviewing and guided opioid weaning (MI+GOW) to promote opioid cessation and prevent opioid misuse after surgery in a high-risk cohort (preoperative opioid users) and Aim 3) will characterize treatment interactions with participant attributes (motivation for change, depressive symptoms), and longitudinal changes in depressive (self-loathing symptoms) throughout treatment. This novel intervention fills a critical knowledge gap regarding evidence- based methods for postoperative opioid tapering. 220 patients undergoing total hip or knee replacement taking opioids both prior to and 2 weeks after surgery, will be randomized to EUC or MI+GOW after surgery and followed for one year. The proposed research will have a marked impact on public health laying the foundation for implementation of preoperative psychological screening, preoperative psychological optimization, and development of additional interventions for patients at risk for chronic opioid use and misuse after surgery.